Nucleoside analogues as a class have a well-established regulatory history, with many currently approved by the US Food and Drug Administration (US FDA) for treating viruses and cancer, including but not limited to leukemias, lymphoms, cervical cancer, skin cancers, human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV), herpes simplex, varicella zoster virus (VZV) and respiratory syncytial virus (RSV), among others. However, there is a current challenge in developing cancer and antiviral therapies to inhibit cancer cells or viral replication without injuring the host cell.
Currently there are no approved treatments or vaccines for human coronaviruses (HCoVs) or potentially lethal zoonotic coronaviruses (CoVs), such as severe acute respiratory syndrome (SARS) or Middle East respiratory syndrome (MERS). HCoVs were first identified in the 1960s with only two species known at the time, HCoV-229E and HCoV-OC43. These viruses are known to cause a large number of common colds with typically mild symptoms, with the exception of those suffering from other illnesses, particularly immunocompromised systems. (9) In 2002 a new coronavirus pathogen associated with severe lung disease emerged in Guangzhou, and later spread to Southern China and Hong Kong. The new virus was named SARS-CoV, (10) and before the end of the outbreak over 8,000 cases were confirmed in several countries and with almost 8,000 fatalities. Since then two additional coronaviruses, HCoV-NL63 and HCoV-HKU1, were discovered in humans and most recently, in 2012, MERS-CoV was identified as a second zoonotic coronavirus that can cause lethal respiratory infections in humans.
The current MERS outbreak has been ongoing for almost three years, with well over a thousand confirmed cases having been documented, with a mortality rate of about 40%. (1) Since the 2002-2003 SARS outbreaks, there have been extensive efforts to target the coronavirus family, including the screening of libraries of already approved antiviral drugs such as acyclovir (ACV), ganciclovir, lamivudine, and zidovudine. Unfortunately, none of these well-known antiviral drugs exhibited any activity against SARS-CoV or MERS-CoV in vitro. (2)
The SARS-CoV screening efforts did, however, yield a small number of leads including the nucleoside analogue ribavirin, a guanosine-like analogue that has exhibited broad-spectrum antiviral activity. (2-7) Ribavirin was found to inhibit coronavirus replication in vitro, but with an inhibitory concentration much higher (500-5000 μg/ml) than that needed to inhibit other viruses (50-100 μg/ml). Consequently, it does not appear to represent a viable treatment option. Moreover, a recent study has suggested that in the case of the coronaviruses, ribavirin's antiviral activity is not primarily due to lethal mutagenesis, but rather to its effect on the cell's Guanosine-5′-triphosphate (GTP) biosynthesis. (8) Beyond these studies, there are few reports of nucleoside inhibitors being studied or developed to combat coronavirus infection.
The need for new and more effective antiviral therapeutics, particularly those targeting emerging and reemerging infectious diseases and pathogens continues to increase. Thus, in light of the above discussion, there is a need for discovering and providing new and more efficient antiviral drugs.